Category: 3. Business

In a new trial, patients newly diagnosed with acute myeloid leukemia (AML) fared significantly better with a combined regimen of azacitidine and venetoclax compared with conventional induction chemotherapy. The azacitidine–venetoclax combination (known as aza-ven) is the standard of care for older adults who are not fit enough for intensive chemotherapy. The trial is the first to test the superiority of this regimen to intensive induction chemotherapy, the current standard for fit patients.

Our study met its primary endpoint, demonstrating that aza-ven improves event-free survival. It also leads to higher rates of overall response and composite complete response than intensive induction chemotherapy in younger, intensive-chemotherapy-eligible patients. A greater proportion of patients successfully proceeded to transplant following response with less early mortality, significantly improved quality of life during initial treatment, and less time in the hospital.”

Amir Fathi, MD, lead study author, director of the Center for Leukemia at Mass General Brigham Cancer Institute and associate professor of medicine, Harvard Medical School, Boston

AML is a cancer of the bone marrow that causes an overabundance of abnormal white blood cells and impedes the production of healthy blood cells. Hematopoietic stem cell transplantation can cure AML, but this option is not available to everyone, and almost all patients must undergo initial treatments to reduce cancer in the bone marrow before proceeding to transplant. Intensive induction chemotherapy with cytarabine and anthracyclines has long stood as the standard frontline treatment, but this treatment requires patients to spend about a month in the hospital and carries a high risk of infection, bleeding, and other complications and side effects.

Azacitidine is a chemotherapy drug that has been used for years, in injectable forms, for older patients with AML. Venetoclax is an oral targeted therapy that inhibits the BCL-2 protein, which is involved in cancer cell survival. The two agents are generally well tolerated and can be administered and managed safely on an outpatient basis over time.

In the trial, 172 adult patients were randomly assigned to receive either aza-ven or standard intensive induction chemotherapy. The results were significantly better in the aza-ven arm for the trial’s primary endpoint, event-free survival (EFS), with events defined as relapse, disease progression, disease refractoriness prompting change in therapy, or death. With a median follow-up of just under 22 months, EFS was significantly longer in the aza-ven arm; the median EFS was more than 14 months among those receiving aza-ven compared with a median of just over six months for those receiving induction chemotherapy. The effect of aza-ven remained protective even after adjusting for other variables, and at one year, 53% of those in the aza-ven arm met criteria for EFS compared with 36% of those in the control arm. 

Patients whose cancer had certain characteristics, including core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless age 60 or over), were excluded from the trial. As a result, the study reflects a patient population of predominantly intermediate-to-high-risk AML, although all patients were fit enough to undergo intensive induction chemotherapy.

“I believe the data support the use of this treatment in this population,” said Dr. Fathi. “It applies to adverse risk and intermediate risk patients who don’t have FLT3 mutations. That doesn’t mean that other patient populations may not benefit, but they require their own focused study.”

Participants receiving aza-ven experienced a higher overall response to treatment than those receiving induction chemotherapy, with 88% of those in the aza-ven arm seeing an overall response and 78% seeing a composite complete response, compared with 62% and 54% in the control arm, respectively. They were also more likely to progress to a transplant, which occurred in 61% of those receiving aza-ven and 40% of those receiving induction chemotherapy.

The rate of grade 3 or 4 therapy-related adverse events was similar between study arms. No patients who received aza-ven died within 60 days, while 5% of those in the control group died by this timepoint. Hospitalization was also longer among patients in the control group. Ten percent of patients in the induction arm required admission to the intensive care unit during their index hospitalization, compared with zero in the aza-ven arm. Patients in the aza-ven arm also reported a lower symptom burden and lower rates of depression at two weeks, according to quality of life assessments.

The researchers plan to conduct further analyses to compare costs, the rate of infectious complications, and other factors that may inform treatment decisions for this patient population. In addition, they will assess the use of measurable residual disease status to provide key prognostic and predictive information across arms of the study and inform the optimal amount of treatment needed for aza-ven prior to transplant. 

The study was investigator-initiatied; Genentech and AbbVie Inc. (maker of venetoclax), provided the study drug and funding to support research staff.

Amir Fathi, MD, of Mass General Brigham Cancer Institute and Harvard Medical School will present this study on Sunday, December 7, 2025, at 3:45 p.m. Eastern time during the Plenary Scientific Session in West Hall D2 of the Orange County Convention Center.

Source:

American Society of Hematology

SHANGHAI, Dec. 7, 2025 /PRNewswire/ — CARsgen Therapeutics Holdings Limited (Stock Code: 2171.HK), a company focused on developing innovative CAR T-cell therapies, announced that clinical data from its allogeneic BCMA-targeted CAR T-cell product candidate, CT0596, for the treatment of relapsed/refractory multiple myeloma (R/R MM) was presented in a poster at the 67th American Society of Hematology5 achieved PR or better. Six patients  (ASH) Annual Meeting. The poster was titled “A First-in-Human Study of CT0596, an Allogeneic CAR T-Cell Therapy Targeting BCMA, in Patients with Relapsed/Refractory Multiple Myeloma.” The publication number was 2296.

This clinical trial (NCT06718270) enrolled 8 patients with R/R MM in the dose-escalation phase who received CT0596 infusion. The median number of prior lines of therapy was 4.5 (range: 3-9). Enrollment was not restricted by NKG2A expression levels. Regarding lymphodepletion, 6 patients received full-dose lymphodepletion with fludarabine (30 mg/m²/day) and cyclophosphamide (500 mg/m²/day) for 3 consecutive days, while 2 patients received reduced-dose lymphodepletion. CT0596 was administered at dose levels of 1.5×10⁸ (n=1), 3×10⁸ (n=5), and 4.5×10⁸ CAR-T cells (n=2), with one patient receiving two infusions.

As of August 31, 2025, all 8 infused patients were evaluable for efficacy, with a median follow-up of 4.14 months (range: 0.9-7.9 months). Six patients achieved a partial response (PR) or better: 3 achieved complete response/stringent complete response (CR/sCR) (all in the full-dose lymphodepletion group), 1 achieved very good partial response (VGPR), and 2 achieved PR. Among the 6 patients who received full-dose lymphodepletion, 5 achieved PR or better. Six patients  in the full-dose lymphodepletion group achieved minimal residual disease (MRD)-negativity at Week 4. Patient 01 maintained ongoing sCR and MRD-negativity as of Month 8. Patient 04 achieved PR with resolution of extramedullary disease following the second infusion. CAR-T cell expansion was observed in all 8 patients. Among the two patients who received the 4.5×10⁸ dose, one achieved sCR, and the other exhibited deepening response to VGPR.

CT0596 demonstrated a manageable safety profile. Four patients experienced Grade 1 cytokine release syndrome (CRS); no Grade 2 or higher CRS was observed. No immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) was reported. No dose-limiting toxicities, treatment discontinuations, or deaths were observed.

The study is still in the dose-exploration phase. The lymphodepletion regimen has been determined, and higher cell doses are being explored to further define the recommended dose (RD). The company plans to initiate a Phase 1b registrational study for CT0596 in 2026.

About CT0596

CT0596 is an allogeneic BCMA-targeted CAR-T therapy developed using CARsgen’s proprietary THANK-u Plus™ platform. It is currently being evaluated in investigator-initiated trials for relapsed/refractory multiple myeloma (R/R MM) or plasma cell leukemia (PCL). CT0596 demonstrated preliminary favorable tolerability and encouraging efficacy signals. Further investigation is planned in additional plasma cell malignancies and autoimmune diseases mediated by autoreactive plasma cells. The company anticipates submitting an Investigational New Drug (IND) application in the second half of 2025.

About CARsgen Therapeutics Holdings Limited

CARsgen is a biopharmaceutical company focusing on developing innovative CAR T-cell therapies to address the unmet clinical needs including but not limited to hematologic malignancies, solid tumors and autoimmune diseases. CARsgen has established end-to-end capabilities for CAR T-cell research and development covering target discovery, preclinical research, product clinical development, and commercial-scale production. CARsgen has developed novel in-house technologies and a product pipeline with global rights to address challenges faced by existing CAR T-cell therapies. Efforts include improving safety profile, enhancing the efficacy in treating solid tumors, and reducing treatment costs, etc. CARsgen’s mission is to be a global biopharmaceutical leader that provides innovative and differentiated cell therapies for patients worldwide and makes cancer and other diseases curable.

Forward-looking Statements

All statements in this press release that are not historical fact or that do not relate to present facts or current conditions are forward-looking statements. Such forward-looking statements express the Group’s current views, projections, beliefs and expectations with respect to future events as of the date of this press release. Such forward-looking statements are based on a number of assumptions and factors beyond the Group’s control. As a result, they are subject to significant risks and uncertainties, and actual events or results may differ materially from these forward-looking statements and the forward-looking events discussed in this press release might not occur. Such risks and uncertainties include, but are not limited to, those detailed under the heading “Principal Risks and Uncertainties” in our most recent annual report and interim report and other announcements and reports made available on our corporate website, https://www.carsgen.com. No representation or warranty is given as to the achievement or reasonableness of, and no reliance should be placed on, any projections, targets, estimates or forecasts contained in this press release.

SOURCE CARsgen Therapeutics

The maker of ChatGPT is no longer seen as being on the cutting edge of AI technology and is facing questions about its lack of profitability and the need to grow rapidly to pay for its massive spending commitments. Meanwhile, Google’s parent is emerging as a deep-pocketed competitor with tentacles in every part of the AI trade.

“OpenAI was the golden child earlier this year, and Alphabet was looked at in a very different light,” said Brett Ewing, chief market strategist at First Franklin Financial Services. “Now sentiment is much more tempered toward OpenAI.” 

As a result, the shares of companies in OpenAI’s orbit — principally Oracle Corp., CoreWeave Inc., and Advanced Micro Devices Inc., but also Microsoft Corp., Nvidia Corp. and SoftBank, which has an 11% stake in the company — are coming under heavy selling pressure. Meanwhile, Alphabet’s momentum is boosting not only its stock price, but also those it’s associated with like Broadcom Inc., Lumentum Holdings Inc., Celestica Inc., and TTM Technologies Inc.

Read More: Alphabet’s AI Strength Fuels Biggest Quarterly Jump Since 2005

The shift has been dramatic in magnitude and speed. Just a few weeks ago, OpenAI was sparking huge rallies in any company related to it. Now, those connections look more like an anchor. It’s a change that carries wide-ranging implications, given how central the closely held company has been to the AI mania that has driven the stock market’s three-year rally. 

“A light has been shined on the complexity of the financing, the circular deals, the debt issues,” Ewing said. “I’m sure this exists around the Alphabet ecosystem to a certain degree, but it was exposed as pretty extreme for OpenAI’s deals, and appreciating that was a game-changer for sentiment.”

A basket of companies connected to OpenAI has gained 74% in 2025, which is impressive but far shy of the 146% jump by Alphabet-exposed stocks. The technology-heavy Nasdaq 100 Index is up 22%. 

The skepticism surrounding OpenAI can be dated to August, when it unveiled GPT-5 to mixed reactions. It ramped up last month when Alphabet released the latest version of its Gemini AI model and got rave reviews. As a result, OpenAI Chief Executive Officer Sam Altman declared a “code red” effort to improve the quality of ChatGPT, delaying other projects until it gets its signature product in line.

‘All the Pieces’

Alphabet’s perceived strength goes beyond Gemini. The company has the third highest market capitalization in the S&P 500 and a ton of cash at its disposal. It also has a host of adjacent businesses, like Google Cloud and a semiconductor manufacturing operation that’s gaining traction. And that’s before you consider the company’s AI data, talent and distribution, or its successful subsidiaries like YouTube and Waymo.

“There’s a growing sense that Alphabet has all the pieces to emerge as the dominant AI model builder,” said Brian Colello, technology equity senior strategist at Morningstar. “Just a couple months ago, investors would’ve given that title to OpenAI. Now there’s more uncertainty, more competition, more risk that OpenAI isn’t the slam-dunk winner.”

Read More: Alphabet’s AI Chips Are a Potential $900 Billion ‘Secret Sauce’

Representatives for OpenAI and Alphabet didn’t respond to requests for comment.

The difference between being first or second place goes beyond bragging rights, it also has significant financial ramifications for the companies and their partners. For example, if users gravitating to Gemini slows ChatGPT’s growth, it will be harder for OpenAI to pay for cloud-computing capacity from Oracle or chips from AMD.

By contrast, Alphabet’s partners in building out its AI effort are thriving. Shares of Lumentum, which makes optical components for Alphabet’s data centers, have more than tripled this year, putting them among the 30 best performers in the Russell 3000 Index. Celestica provides the hardware for Alphabet’s AI buildout, and its stock is up 252% in 2025. Meanwhile Broadcom — which is building the tensor processing unit, or TPU, chips Alphabet uses — has seen its stock price leap 68% since the end of last year.

OpenAI has announced a number of ambitious deals in recent months. The flurry of activity “rightfully brought scrutiny and concern over whether OpenAI can fund all this, whether it is biting off more than it can chew,” Colello said. “The timing of its revenue growth is uncertain, and every improvement a competitor makes adds to the risk that it can’t reach its aspirations.”

In fairness, investors greeted many of these deals with excitement, because they appeared to mint the next generation of AI winners. But with the shift in sentiment, they’re suddenly taking a wait-and-see attitude.

“When people thought it could generate revenue and become profitable, those big deal numbers seemed possible,” said Brian Kersmanc, portfolio manager at GQG Partners, which has about $160 billion in assets. “Now we’re at a point where people have stopped believing and started questioning.”

Kersmanc sees the AI euphoria as the “dot-com era on steroids,” and said his firm has gone from being heavily overweight tech to highly skeptical.

Self-Inflicted Wounds 

“We’re trying to avoid areas of over-hype and a lot of those were fueled by OpenAI,” he said. “Since a lot of places have been touched by this, it will be a painful unwind. It isn’t just a few tech names that need to come down, though they’re a huge part of the index. All these bets have parallel trades, like utilities, with high correlations. That’s the fear we have, not just that OpenAI spun up this narrative, but that so many things were lifted on the hype.”

OpenAI’s public-relations flaps haven’t helped. The startup’s Chief Financial Officer Sarah Friar recently suggested the US government “backstop the guarantee that allows the financing to happen,” which raised some eyebrows. But she and Altman later clarified that the company hasn’t requested such guarantees. 

Then there was Altman’s appearance on the “Bg2 Pod,” where he was asked how the company can make spending commitments that far exceed its revenue. “If you want to sell your shares, I’ll find you a buyer — I just, enough,” was the CEO’s response.

Read More: Sam Altman’s Business Buddies Are Getting Stung

Altman’s dismissal was problematic because the gap between OpenAI’s revenue and its spending plans between now and 2033 is about $207 billion, according to HSBC estimates.

“Closing the gap would need one or a combination of factors, including higher revenue than in our central case forecasts, better cost management, incremental capital injections, or debt issuance,” analyst Nicolas Cote-Colisson wrote in a research note on Nov. 24. Considering that OpenAI is expected to generate revenue of more than $12 billion in 2025, its compute cost “compounds investor nervousness about associated returns,” not only for the company itself, but also “for the interlaced AI chain,” he wrote. 

To be sure, companies like Oracle and AMD aren’t solely reliant on OpenAI. They operate in areas that continue to see a lot of demand, and their products could find customers even without OpenAI. Furthermore, the weakness in the stocks could represent a buying opportunity, as companies tied to ChatGPT and the chips that power it are trading at a discount to those exposed to Gemini and its chips for the first time since 2016, according to a recent Wells Fargo analysis. 

“I see a lot of untapped demand and penetration across industries, and that will ultimately underpin growth,” said Kieran Osborne, chief investment officer at Mission Wealth, which has about $13 billion in assets under management. “Monetization is the end goal for these companies, and so long as they work toward that, that will underpin the investment case.”

“Our expectation of solid growth and easier monetary and fiscal policies supports a risk-on tilt in our multi-asset portfolios. We remain overweight stocks and credit,” said Sylvia Sheng, global multi-asset strategist at JPMorgan Asset Management.

“We are playing the powerful trends in place and are bullish through the end of next year,” said David Bianco, Americas chief investment officer at DWS. “For now we are not contrarians.”

“Start the year with sufficient exposure, even over-exposure to equities, predominantly in emerging market equities,” said Nannette Hechler-Fayd’herbe, EMEA chief investment officer at Lombard Odier. “We don’t expect a recession in 2026 to unfold.”

Those assessments came from Bloomberg News interviews with 39 investment managers across the US, Asia and Europe, including at BlackRock Inc., Allianz Global Investors, Goldman Sachs Group Inc. and Franklin Templeton.

More than three-quarters of the allocators were positioning portfolios for a risk-on environment through 2026. The thrust of the bet is that resilient global growth, further developments in artificial intelligence, accommodative monetary policy and fiscal stimulus will deliver outsize returns in all fashion of global equity markets. 

The call is not without risks, including simply its pervasiveness among the respondents, along with their overall high degree of assuredness. The view among the institutional investors also aligns with that of sell-side strategists around the globe. 

Should the bullishness play out as expected, it would deliver a stunning fourth straight year of bumper returns for the MSCI All-Country World Index. That would extend a run that’s added $42 trillion in market capitalization since the end of 2022 — the most value created for equity investors in history. 

That’s not to say the optimism is without merit. The artificial intelligence trade has added trillions in market value to dozens of firms plying the industry, but just three years after ChatGPT broke into the public consciousness, AI remains in the early phase of development.

No Tech Panic

The buy-side managers largely rejected the idea that the technology has blown a bubble in equity markets. While many acknowledged some pockets of froth in unprofitable tech names, 85% of managers said valuations among the Magnificent Seven and other AI heavyweights are not overly inflated. Fundamentals back the trade, they said, which marks the beginning of a new industrial cycle. 

“You can’t call it a bubble when you’re seeing tech companies deliver a massive earnings beat. In fact, earnings from the sector have outstripped all other US stocks,” said Anwiti Bahuguna, global co-chief investment officer at Northern Trust Asset Management.

As such, investors expect the US to remain the engine of the rally. 

“American exceptionalism is far from dead,” said Jose Rasco, chief investment officer at HSBC Americas. “As artificial intelligence continues to spread around the globe, the US will be a key participant.” 

Most investors echoed the sentiment expressed by Helen Jewell, international chief investment officer of fundamental equities at BlackRock, who suggested also searching outside the US for meaningful upside.

“The US is where the high-return high-growth companies are, so we have to be realistic about that. But those are already reflected in valuations, and there are probably more interesting opportunities outside the US,” she said.

International Boom

Profits matter above all else for equity investors, and huge bumps in government spending from Europe to Asia have stoked estimates for strong gains in earnings.

“We have begun to see a meaningful broadening of earnings momentum, both across market capitalizations and across regions, including Japan, Taiwan, and South Korea,” said Wellington Management equity strategist Andrew Heiskell. “Looking into 2026, we see clear potential for a revival of earnings growth in Europe and a wider range of emerging markets.”

India is one of the most compelling opportunities for 2026, according to Goldman Sachs Asset Management’s Alexandra Wilson-Elizondo, global co-head and co-chief investment officer of multi-asset solutions.

“We see real potential for India to become the Korea-like re-rating story of 2026, a market that transitions from tactical allocation to strategic core exposure in global portfolios,” she said. 

Nelson Yu, head of equities at AllianceBernstein, said he sees improvements outside of the US that will mandate allocations. He noted governance reform in Japan, capital discipline in Europe and recovering profitability in some emerging markets.

Small Cap Optimism

At the sector level, the investors are looking for AI proxies, notably among clean energy providers that can help meet the technology’s ravenous demand for power. Smaller stocks are also finding favor.

“The earnings outlook has brightened for small-capitalization stocks, industrials and financials,” said Stephen Dover, chief market strategist and head of Franklin Templeton Institute. “Small-cap stocks and industrials, which are typically more highly leveraged than the rest of the market, will see profitability rise as the Federal Reserve trims interest rates and debt servicing costs fall.”

Over at Santander Asset Management, Francisco Simón sees earnings growth of more than 20% for US small caps after years of underperformance. Reflecting the optimism, the Russell 2000 Index of such equities recently hit a record high.

Meanwhile, the combination of low valuations and strong fundamentals makes health care one of the most compelling contrarian opportunities in a bullish cycle, a preponderance of managers said.  

“Health-care related sectors can surprise to the upside in the US markets,” said Jim Caron, chief investment officer of cross-asset solutions at Morgan Stanley Investment Management. “This is a mid-term election year and policy may at the margin support many companies. Valuations are still attractive and have a lot of catch up to do.”

Virtually every allocator struck at least a note of caution about what lies ahead. The top worry among them was a rekindling of inflation in the US. If the Fed is forced by rising prices to abruptly pause or even end its easing cycle, the potential for turbulence is high.

“A scenario — which is not our base case — whereby US inflation rebounds in 2026 would constitute a double whammy for multi-asset funds as it would penalize both stocks and bonds. In this sense it would be much worse than an economic slowdown,” said Amélie Derambure, senior multi-asset portfolio manager at Amundi SA. 

“The way investors are headed for 2026, they need to have the Fed on their side,” she added.

Trade Caution

Another worry is around President Donald Trump’s capriciousness, particularly when it comes to trade. Any flareup in his trade spats that fuels inflation through heightened tariffs would weigh on risk assets. 

Oil and gas producers remain unloved by the group, though that could change if a major geopolitical event upends supply lines. While such an outcome would bolster those sectors, the overall impact would likely be negative for risk assets, they said.

“Any geopolitical situation that can affect the price of oil is what will have the largest impact on the financial markets. Clearly both the Middle East and the Ukraine/Russia situations can impact oil prices,” said Scott Wren, senior global market strategist at Wells Fargo Investment Institute.

Multiple respondents flagged European autos as a “no-go” area for 2026, citing intense competitive pressure from Chinese carmakers, margin compression and structural challenges in the transition to electric vehicles. 

“Personally I don’t believe for a minute that there will be a rebound in the sector,” said Isabelle de Gavoty at Allianz GI. 

Outside of those worries, most asset managers simply believe that there’s little reason to fret about the upward momentum being interrupted — outside, of course, from the contrarian signal such near-uniform bullishness sends.

“Everyone seems to be risk-on at the moment, and that worries me a bit in the sense that the concentration of positions creates less tolerance for adverse surprises,” said Amundi’s Derambure.  

Story Continues

The noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca) elicited objective response rate (ORR) of 81.6% (95% CI, 76.5%–85.9%) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with a covalent BTK inhibitor, according to findings from the final analysis of the phase 1/2 BRUIN trial (NCT03740529) that were presented at the 2025 ASH Annual Meeting.¹

Best responses included complete response (CR; n = 11; 3.9%), CR with incomplete blood count recovery (n = 1; 0.4%), non–partial response (PR; n = 3; 1.1%), PR (n = 189; 67.0%), and PR with lymphocytosis (n = 26; 9.2%). In subgroup analysis, the highest ORRs were seen in patients with deletion 11q (n = 47; ORR, 91.5%; 95% CI, 79.6%–97.6%), complex karyotype (n = 33; ORR, 90.9%; 95% CI, 75.7%–98.1%), and 17p deletion and/or TP53 mutation (n = 104; ORR, 87.5%; 95% CI, 79.6%–93.2%). The populations that appeared to derive the least benefit were patients with mutated PLCg2 (n = 18; ORR, 55.6%; 95% CI, 30.8%–78.5%), unmutated BTK C481 (n = 97; ORR, 74.2%; 95% CI, 64.3%–82.6%), and mutated IGHV (n = 32; ORR, 75.0%; 95% CI, 56.6%–88.5%).

“Pirtobrutinib continues to show favorable efficacy and promising overall survival [OS],” William G. Wierda, MD, PhD, lead study author and Endowed Distinguished Professor Jane and John Justin Distinguished Chair in Leukemia Research in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote in the poster.

Unmet Needs

Intolerance or treatment resistance remains an issue with covalent BTK inhibitors despite their valued integration into the CLL/SLL armamentarium. Pirtobrutinib is a selective, noncovalent BTK inhibitor that was designed to work against common mechanisms associated with resistance to covalent inhibitors.

Earlier findings from the BRUIN trial illustrated the agent’s efficacy and safety in patients with relapsed/refractory disease, including those with prior exposure to covalent inhibition. Data from the trial led to the agent’s accelerated approval from the FDA in December 2023, which was converted to full approval on December 3, 2025.^2,3

The phase 1 dose-escalation and -expansion portion of the trial modeled a 3+3 design, which allowed for intra-patient dose escalation, cohort expansion at doses deemed safe, and treatment with 25 to 300 mg of once daily pirtobrutinib via 28-day cycles.¹ In phase 2, patients received 200 mg of once-daily pirtobrutinib.

A total of 778 patients were enrolled: 166 with mantle cell lymphoma, 317 with CLL/SLL, and 295 with other malignancies. Of the 317 patients with CLL/SLL, 35 were BTK naive, and 282 had been exposed to covalent BTK inhibition. Of the latter group, 154 patients were BCL2 naive, and 128 had received BCL2 inhibition.

Eligible patients were at least 18 years old and had previously treated, active disease in need of therapy, and an ECOG performance status between 0 and 2.

Key end points included safety/tolerability, determination of the maximum tolerated dose/recommended phase 2 dose, pharmacokinetics, ORR, progression-free survival (PFS), time to next treatment (TTNT), and OS.

Baseline characteristics across the board of patients with prior exposure to covalent BTK inhibition, BCL2 inhibition, and those naive to BCL2 inhibition revealed that most were male; had received prior BTK inhibition, anti-CD20 therapy, and chemotherapy; had discontinued treatment because of progressive disease; and had unmutated IGHV.

Efficacy of Pirtobrutinib

The median duration of response (DOR) was 18.4 months (95% CI, 14.8–20.3), and the 36-month DOR rate was 28.0% (95% CI, 21.6%-34.7%). At median follow-up of 49.9 months the median TTNT was 23.2 months (95% CI, 20.3-29.4). The 12-, 24-, 36-, 48-, and 60-month TTNT rates were 74.7%, 49.9%, 34.1%, 23.3%, and 21.5%, respectively.

Median PFS was 18.7 months (95% CI, 16.6–21.8) at median follow-up of 44.2 months. The 12-, 24-, 36-, 48-, and 60-month PFS rates were 67.1%, 38.1%, 25.0%, 21.6%, and 17.6%, respectively. PFS was also subdivided between patients who were BCL2 naive and exposed. The median PFS was 15.9 months (95% CI, 13.6–17.5) in the exposed population and 22.3 months (95% CI, 19.3-27.6) in the naive population. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the exposed cohort were 60.8%, 25.0%, 14.0%, 14.0%, and 14.0%, respectively. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the naive cohort were 72.1%, 47.9%, 32.9%, 27.7%, and 21.7%, respectively.

In all patients who received covalent BTK inhibition, the median OS was not estimable (95% CI, 47.8 months-NE) at a median follow-up of 46.5 months. The 12-, 24-, 36-, 48-, and 60-month OS rates were 85.5%, 72.2%, 62.0%, 56.0%, and 54.2%, respectively.

Safety Profile

The median time on treatment was 20.0 months (IQR, 9.6-37.7). TRAEs leading to dose reduction and discontinuation occurred in 11 (3.9%) and 9 (3.2%) patients, respectively.

All-cause adverse effects (AEs) that occurred in at least 20% of patients included fatigue (any grade, 38.7%; grade ≥3, 1.8%), neutropenia (35.8%; 29.8%), diarrhea (30.5%; 0.4%), cough (29.8%; 0%), contusion (27.7%; 0%), COVID-19 (28.4%; 6.0%), dyspnea (23.4%; 2.5%), nausea (23.4%; 0%), and abdominal pain (21.6%; 2.1%). AEs of interest included infections (76.2%; 36.5%), bruising (31.2%; 0%), rash (25.2%; 1.1%), arthralgia (23.0%; 1.4%), hemorrhage (25.2%; 3.2%), hypertension (16.0%; 5.3%), and atrial fibrillation/flutter (5.0%; 2.1%).

Treatment-related adverse effects (TRAEs) that occurred in at least 20% of patients included fatigue (any grade, 3.9%; grade ≥3, 0%), neutropenia (20.6%; 16.3%), diarrhea (8.9%; 0%), cough (2.1%; 0%), contusion (18.8%; 0%), COVID-19 (0.7%; 0%), dyspnea (0.7%; 0.4%), nausea (3.9%; 0%), and abdominal pain (2.1%; 0.4%). AEs of interest included infections (14.9%; 5.7%), bruising (20.2%; 0%), rash (5.7%; 0.4%), arthralgia (4.6%; 0%), hemorrhage (8.2%; 1.4%), hypertension (3.9%; 0.7%), and atrial fibrillation/flutter (1.4%; 0.7%).

“Pirtobrutinib remains well tolerated with low rates of dose reduction or discontinuation due to TRAEs and low rates of grade 3 or greater hypertension, hemorrhage/hematoma, and atrial fibrillation/atrial flutter, which are risks with covalent BTK inhibitor treatment,” the authors concluded.

DISCLOSURES: No disclosures were listed.

REFERENCES

1. Wierda W, Brown J, Ghia P, et al. Pirtobrutinib in post-BTKi CLL/SLL: final update from the phase 1/2 BRUIN study with more than 5-years follow-up. Blood. 2025;146(suppl 1):2115. doi:10.1182/blood-2025-2115

2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed December 7, 2025. https://tinyurl.com/mec3c3t3

3. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 7, 2025. https://tinyurl.com/46522682